Novel Ligands and Mechanisms to Achieve Selective Nuclear Receptor Activity

说明(申请人提供)：雌激素通过雌激素受体ER？和ER？控制许多目标组织的许多生理和病理过程。虽然在开发具有更理想的选择活性模式的ER配体方面取得了进展，如选择性ER调节剂(SERM)和ER亚型选择性配体，但ER作用方式和途径的多样性提供了耐人寻味但尚未探索的机制，人们应该能够通过这些机制获得具有更高水平所需选择性的新化合物。我们的总体目标是开发有效的ER配体，优化其在三个医学重要领域提供所需的、长期寻求的全方位选择性，通过三种不同的机制实现：(A)通过精心挑选的新型结构配体通过ER介导的脑神经保护；(B)通过雌激素-树突状大分子结合物(EDCs)和设计新颖的小分子选择性地激活核外启动的ER信号通路，提供心血管保护；以及(C)通过结构新颖的配体诱导独特的ER构象，将抗增殖/抗炎活性结合起来，作为雌激素依赖型乳腺癌和子宫内膜异位症的优化治疗。每一项工作都集中在一个独特的机制范例上，并得到了与现有研究小组积极的、持续的合作的支持，这些合作应该会为进一步的临床前开发带来极好的机会。目的：(1)开发具有选择性脑神经保护活性的新型ER配体。我们的ER配体的一个子集，通过内源性自分泌抗炎途径发挥作用，具有神经保护作用，并在多发性硬化症动物模型中发挥作用，逆转既定疾病。我们将发展结构-活性关系，以提高这些新化合物的效力和选择性。(2)开发具有选择性血管、心脏和骨骼保护作用的新型通路特异性内质网配体。我们的EDC阻止激素进入细胞核，只激活核外启动的ER信号通路，但它提供与雌二醇相当的心血管保护，而不刺激子宫或乳腺肿瘤。我们将开发具有口服活性的具有高度稳定性的树枝状大分子和精心设计的具有路径选择性的小分子偶联物。(3)开发结合抗炎和抗增殖活性的新型ER配体，以改善内分泌抵抗型乳腺癌和子宫内膜异位症的治疗。我们的三维ER配体稳定了以前未见过的ER构象，并抑制了激素抗性乳腺癌株和子宫内膜异位症病变。利用结构导向设计，我们将开发出更高效力和更具选择性的化合物。

DESCRIPTION (provided by applicant): Estrogens, acting through the estrogen receptors, ER¿ and ER¿, control many physiological and pathological processes in numerous target tissues. While progress has been made in developing ER ligands having more desirable patterns of selective activity, such as selective ER modulators (SERMs) and ER-subtype selective ligands, the diversity of modes and pathways through which the ERs act offers intriguing but as yet unexplored mechanisms through which one should be able to obtain new compounds having higher levels of desired selectivity. Our overall goal is to develop potent ER ligands optimized to deliver the full range of desired, long sought-after selectivity in three medically important areas, achieved by three distinct mechanisms: (A) brain neuroprotection mediated through ER¿ with carefully selected ligands of novel structure; (B) cardiovascular protection afforded by selective activation of extranuclear-initiated ER signaling pathways by estrogen-dendrimer conjugates (EDCs) and small molecules of novel design; and (C) combined anti-proliferative/anti-inflammatory activity as optimized therapy for estrogen-dependent breast cancer and endometriosis, through unique ER conformations induced by structurally novel ligands. Each effort is centered on a distinct mechanistic paradigm and is supported by active, ongoing collaborations with established research groups that should lead to excellent opportunities for further pre-clinical development. Aims: (1) Develop Novel ER¿ Ligands Having Selective Brain Neuroprotective Activities. A subset of our ER¿ ligands, acting through an endogenous autocrine anti-inflammatory pathway, is neuroprotective and is active in animal models of multiple sclerosis, reversing established disease. We will develop structure-activity relationships to enhance potency and selectivity of these novel compounds. (2) Develop Novel Pathway-Specific ER Ligands that Afford Selective Vascular, Cardiac, and Bone Protection. Our EDC blocks hormone entry into the nucleus and activates only the extranuclear-initiated ER signaling pathway, yet it provides cardiovascular protection equivalent to that of estradiol without stimulation of uterus or breast tumors. We will develop orally active conjugates with highly stable dendrimers and carefully designed small molecules having pathway selectivity. (3) Develop Novel ER Ligands that Combine Anti- Inflammatory and Anti-Proliferative Activities for Improved Therapy for Endocrine-Resistant Breast Cancers and Endometriosis. Our 3-dimensional ER ligands stabilize a previously unseen ER conformation and inhibit hormone-resistant breast cancer lines and endometriotic lesions. Using structure-guided design, we will develop higher potency and more selective compounds.